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Deficits in glutamatergic function are well established in schizophrenia (SZ) as reflected in “input” dysfunction across sensory systems. By contrast, less is known about contributions of the GABAergic system to impairments in excitatory/inhibitory balance. We investigated this issue by measuring contrast thresholds for orientation detection, orientation discriminability, and orientation-tilt-aftereffect curves in schizophrenia subjects and matched controls. These measures depend on the amplitude and width of underlying orientation tuning curves, which, in turn, depend on excitatory and inhibitory interactions. By simulating a well-established V1 orientation selectivity model and its link to perception, we demonstrate that reduced cortical excitation and inhibition are both necessary to explain our psychophysical data. Reductions in GABAergic feedback may represent a compensatory response to impaired glutamatergic input in SZ, or a separate pathophysiological event. We also found evidence for the widely accepted, but rarely tested, inverse relationship between orientation discriminability and tuning width.

To date, no measures are available that permit differentiation of discrete, clinically distinct subtypes of schizophrenia (SZ) with potential differential underlying pathophysiologies. Over recent years, there has been increasing recognition that SZ is heterogeneously associated with deficits in early auditory processing (EAP), as demonstrated using clinically applicable tasks such as tone-matching task (TMT). Here, we pooled TMT performances across 310 SZ individuals and 219 healthy controls (HC), along with clinical, cognitive, and resting-state functional-connectivity MRI (rsFC-MRI) measures. In addition, TMT was measured in a group of 24 patients at symptomatic clinical high risk (CHR) for SZ and 24 age-matched HC (age range 7–27 years). We provide the first demonstration that the EAP deficits are bimodally distributed across SZ subjects (P d = 2.1) and SZ-EAP+ patients (d = 3.4). The SZ-EAP− group predominated among samples drawn from inpatient sites, showed higher levels of cognitive symptoms (PANSS), worse social cognition and a differential deficit in neurocognition (MATRICS battery), and reduced functional capacity. rsFC-MRI analyses showed significant reduction in SZ-EAP− relative to controls between subcortical and cortical auditory regions. As opposed to SZ, CHR patients showed intact EAP function. In HC age-matched to CHR, EAP ability was shown to increase across the age range of vulnerability preceding SZ onset. These results indicate that EAP measure segregates between discrete SZ subgroups. As TMT can be readily implemented within routine clinical settings, its use may be critical to account for the heterogeneity of clinical outcomes currently observed across SZ patients, as well as for pre-clinical detection and efficacious treatment selection.

Deficits in mismatch negativity (MMN) generation are among the best-established biomarkers for cognitive dysfunction in schizophrenia and predict conversion to schizophrenia (Sz) among individuals at symptomatic clinical high risk (CHR). Impairments in MMN index dysfunction at both subcortical and cortical components of the early auditory system. To date, the large majority of studies have been conducted using deviants that differ from preceding standards in either tonal frequency (pitch) or duration. By contrast, MMN to sound location deviation has been studied to only a limited degree in Sz and has not previously been examined in CHR populations. Here, we evaluated location MMN across Sz and CHR using an optimized, multi-deviant pattern that included a location-deviant, as defined using interaural time delay (ITD) stimuli along with pitch, duration, frequency modulation (FM) and intensity deviants in a sample of 42 Sz, 33 CHR and 28 healthy control (HC) subjects. In addition, we obtained resting state functional connectivity (rsfMRI) on CHR subjects. Sz showed impaired MMN performance across all deviant types, along with strong correlation between MMN deficits and impaired neurocognitive function. In this sample of largely non-converting CHR subjects, no deficits were observed in either pitch or duration MMN. By contrast, CHR subjects showed significant impairments in location MMN generation particularly over right hemisphere and significant correlation between impaired location MMN and negative symptoms including deterioration of role function. In addition, significant correlations were observed between location MMN and rsfMRI involving brainstem circuits. In general, location detection using ITD stimuli depends upon precise processing within midbrain regions and provides a rapid and robust reorientation of attention. Present findings reinforce the utility of MMN as a pre-attentive index of auditory cognitive dysfunction in Sz and suggest that location MMN may index brain circuits distinct from those indexed by other deviant types.

We tested two metabotropic glutamate receptor 2/3 (mGluR2/3) agonist prodrugs – pomaglumetad (POMA) and TS-134 – including a high-dose of POMA that was four times the dose tested in the failed phase schizophrenia III trials – in two proof of mechanism, Phase Ib studies using identical pharmacoBOLD target-engagement methodology.The POMA study was a double-blind, NIMH-sponsored, 10-day study of 80 or 320 mg/d POMA or placebo (1:1:1 ratio), designed to detect d>0.8 sd between-group effect-size differences. The TS-134 study was a single-blind, industry-sponsored, 6-day study of 20 or 60 mg/d TS-134 or placebo (5:5:2 ratio), designed to permit effect-size estimation for future studies. Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and Brief Psychiatric Rating Scale (BPRS).95 healthy controls were randomized to POMA and 63 to TS-134. High-dose POMA had significant within and between-group reduction in ketamine-induced BPRS total symptoms (pHigh-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed. TS-134 20 mg showed evidence of symptom reduction and target engagement, indicating a curvilinear dose-response curve. These results warrant further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

Neurofilament (NFL) proteins have recently been found to play unique roles in synapses. NFL is known to interact with the GluN1 subunit of N-methyl-d-aspartic acid (NMDAR) and be reduced in schizophrenia though functional consequences are unknown. Here we investigated whether the interaction of NFL with GluN1 modulates synaptic transmission and schizophrenia-associated behaviors. The interaction of NFL with GluN1 was assessed by means of molecular, pharmacological, electrophysiological, magnetic resonance spectroscopy (MRS), and schizophrenia-associated behavior analyses. NFL deficits cause an NMDAR hypofunction phenotype including abnormal hippocampal function, as seen in schizophrenia. NFL−/− deletion in mice reduces dendritic spines and GluN1 protein levels, elevates ubiquitin-dependent turnover of GluN1 and hippocampal glutamate measured by MRS, and depresses hippocampal long-term potentiation. NMDAR-related behaviors are also impaired, including pup retrieval, spatial and social memory, prepulse inhibition, night-time activity, and response to NMDAR antagonist, whereas motor deficits are minimal. Importantly, partially lowering NFL in NFL+/− mice to levels seen regionally in schizophrenia, induced similar but milder NMDAR-related synaptic and behavioral deficits. Our findings support an emerging view that central nervous system neurofilament subunits including NFL in the present report, serve distinctive, critical roles in synapses relevant to neuropsychiatric diseases.

Schizophrenia (Sz) is a mental health disorder characterized by severe cognitive, emotional, social, and perceptual deficits. Visual deficits are found in tasks relying on the magnocellular/dorsal stream. In our first experiment we established deficits in global motion processing in Sz patients compared to healthy controls. We used a novel task in which background optic flow produces a distortion of the apparent trajectory of a moving stimulus, leading control participants to provide biased estimates of the true motion trajectory under conditions of global stimulation. Sz patients were significantly less affected by the global background motion, and reported trajectories that were more veridically accurate than those of controls. In order to study the mechanism of this effect, we performed a second experiment where we applied transcranial electrical stimulation over area MT+ to selectively modify global motion processing of optic flow displays in healthy participants. Cathodal and high frequency random noise stimulation had opposite effects on trajectory perception in optic flow. The brain stimulation over a control site and in a control task revealed that the effect of stimulation was specific for global motion processing in area MT+. These findings both support prior studies of impaired early visual processing in Sz and provide novel approaches for measurement and manipulation of the underlying circuits. Electronic supplementary material The online version of this article (10.1007/s10548-018-0639-6) contains supplementary material, which is available to authorized users.

Patients with schizophrenia show response inhibition deficits equal to or greater than those seen in impulse-control disorders, and these deficits contribute to poor outcome. However, little is known about the circuit abnormalities underlying this impairment. To address this, we examined stop signal task performance in 21 patients with schizophrenia and 21 healthy controls using event related potential (ERP) and resting state functional connectivity. Patients showed prolonged stop signal reaction time (SSRT) and reduced N1, N2, and P3 amplitudes compared to controls. Across groups, P3 amplitudes were maximal after SSRT (i.e., after the time associated with the decision to stop occurred), suggesting that this component indexed response monitoring. Multiple regression analyses showed that longer SSRTs were independently related to 1) patient status, 2) reduced N1 amplitude on successful stop trials and 3) reduced anticorrelated resting state functional connectivity between visual and frontoparietal cortical networks. This study used a combined multimodal imaging approach to better understand the network abnormalities that underlie response inhibition in schizophrenia. It is the first of its kind to specifically assess the brain's resting state functional architecture in combination with behavioral and ERP methods to investigate response inhibition in schizophrenia., Highlights • People with schizophrenia show deficits in response inhibition measured using behavioral and ERP methods. • Behavioral and ERP measures of response inhibition are correlated. • Patient status, reduced N1, and higher resting state functional connectivity separately predicted poorer response inhibition. • This study underscores the value of using multimodal imaging to understand response inhibition deficits in schizophrenia.

The ability to search for and detect social cues, such as facial expressions of emotion, is critical to the understanding of complex dynamic social situations. This ability involves the coordinated actions of multiple cognitive domains, including face-emotion processing, mentalization, and visual attention. Individuals with schizophrenia are generally impaired in social cognition, and have been shown to have deficits in all of these domains. However, the whether the neural substrates of these impairments are shared or separate remains unclear. One candidate region for a shared substrate is the right temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS), which contains areas belonging to all of the cortical networks underlying these domains. Here we use functional MRI to examine differences in cortical activity evoked by a naturalistic movie, and link these results to impaired visual scanning and social cognition. 27 schizophrenia participants and 21 healthy controls watched a 15-minute clip of the movie "The Good, the Bad, and the Ugly" while high resolution multiband BOLD-fMRI activity was recorded. Inter-subject correlation was used to measure the evoked activity. BOLD-fMRI activity was also correlated with motion content in the movie, with the average activity in other cortical areas, and with frequency of saccades made during the movie. Visual scanning performance was measured in a separate behavioral experiment, and social cognition measured by The Awareness of Social Inference Test (TASIT). Contrasting the groups revealed that the TPJ-pSTS has the largest engagement deficit in both cortical hemispheres in schizophrenia patients versus healthy controls. Follow-up analyses find that brain activity in this region is less correlated with the motion content of the movie, that this region is abnormally synchronized to the other cortical areas involved in the cognitive domains underlying visual scanning of social scenes, and that activity this region is less correlated with the saccades made during the movie. Lastly, schizophrenia participant visual scanning performance of this clip was impaired compared to healthy controls, and correlated across the two groups with social cognition. These results indicate that the TPJ-pSTS plays less of an integral role in the coordination of face-emotion processing, mentalization, and visual attention in schizophrenia participants versus healthy controls. This functional deficit then impacts the visual scanning of a complex dynamic visual scenes, which in turn affects the comprehension of that scene. These findings indicating that the TPJ-pSTS is potentially the shared substrate for all of these deficits will lead to new treatments targeting this region to improve social cognition in individuals with schizophrenia.

Deficits in early auditory processing (EAP) are a core component of schizophrenia (SZ) and contribute significantly to impaired overall function. Here, we evaluate the potential contributions of EAP-related impairments in reading to functional capacity and outcome, relative to effects of auditory social cognitive and general neurocognitive dysfunction. Participants included 30-SZ and 28-controls of similar age, sex, and educational achievement. EAP was assessed using an auditory working memory (tone-matching) task. Phonological processing and reading Fluency were assessed using the Comprehensive Test of Phonological Processing and Woodcock-Johnson reading batteries, respectively. Auditory-related social cognition was assessed using measures of emotion/sarcasm recognition. Functional capacity and outcome were assessed using the UCSD Performance-based Skills Assessment and Specific Level of Functioning scale, respectively. fMRI resting-state functional-connectivity (rsFC) was used to evaluate potential underlying substrates. As predicted, SZ patients showed significant and interrelated deficits in both phonological processing (d = 0.74, p = 0.009) and reading fluency (d = 1.24, p d = 0.35, p = 0.31) was intact. In SZ, deficits in EAP and phonological reading ability significantly predicted reduced functional capacity, but not functional outcome. By contrast, deficits in reading fluency significantly predicted impairments in both functional capacity and functional outcome. Moreover, deficits in reading fluency correlated with rsFC alterations among auditory thalamus, early auditory and auditory association regions. These findings indicate significant contributions of EAP deficits and functional connectivity changes in subcortical and early auditory regions to reductions in reading fluency, and of impaired reading ability to impaired functional outcome in SZ.

International audience; Patients with schizophrenia (SZ) display deficits in both basic non-verbal auditory processing and source-monitoring of speech. To date, the contributions of basic auditory deficits to higher-order cognitive impairments, such as source-monitoring, and to clinical symptoms have yet to be elucidated. The aim of this study was to investigate the deficits and relationships between basic auditory functions, source-monitoring performances, and clinical symptom severity in SZ. Auditory processing of 4 psychoacoustic features (pitch, intensity, amplitude, length) and 2 types of source-monitoring (internal and reality monitoring) performances were assessed in 29 SZ and 29 healthy controls. Clinical symptoms were evaluated in patients with the Positive And Negative Syndrome Scale. Compared to the controls, SZ individuals in showed significant reductions in both global basic auditory processing (p < .0005, d = 1.16) and source-monitoring (p < .0005, d = 1.24) abilities. Both deficits correlated significantly in patients and across groups (all p < .05). Pitch processing skills were negatively correlated with positive symptom severity (r = -0.4, p < .05). A step-wise regression analysis showed that pitch discrimination was a significant predictor of source-monitoring performance. These results suggest that cognitive mechanisms associated with the discrimination of basic auditory features are most compromised in patients with source-monitoring disability. Basic auditory processing may index pathophysiological processes that are critical for optimal source-monitoring in schizophrenia and that are involved in positive symptoms.

Deficits in auditory processing contribute significantly to impaired functional outcome in schizophrenia (SZ), but mediating factors remain under investigation. Here we evaluated two hierarchical components of early auditory processing: pitch-change detection (i.e. identifying if 2 tones have “same” or “different” pitch), which is preferentially associated with early auditory cortex, and serial pitch-pattern detection (i.e. identifying if 3 tones have “same” or “different” pitch, and, if “different”, which one differed from the others), which depends also on auditory association regions. Deficits in pitch-change detection deficits in SZ have been widely reported and correlated with higher auditory disturbances such as Auditory Emotion Recognition (AER). Deficits in serial pitch-pattern discrimination have been less studied. Here, we investigated both pitch perception components, along with integrity of AER in SZ patients vs. controls using behavioral paradigms. We hypothesized that the deficits could be viewed as hierarchically organized in SZ, with deficits in low-level function propagating sequentially through subsequent levels of processing. Participants included 27 SZ and 40 controls. The magnitude of the deficits in SZ participants was large in both the pitch-change (d = 1.15) and serial pitch-pattern tasks (d = 1.21) with no significant differential task effect. The effect size of the AER deficits was extremely large (d = 2.82). In the SZ group, performance in both pitch tasks correlated significantly with impaired AER performance. However, a mediation analysis showed that serial pitch-pattern detection mediated the relationship between simpler pitch-change detection and AER in patients. Findings are consistent with hierarchical models of cognitive dysfunction in SZ with deficits in early information processing contributing to higher level impairments. Furthermore, findings are consistent with recent neurophysiological results suggesting similar level impairments for processing of simple vs. more complex tonal dysfunction in SZ.

BACKGROUND: Face processing deficits characterize schizophrenia, including in prodromal stages. Baseline face processing deficits predict psychosis onset in clinical high-risk (CHR) youths, specifically in fear/anger processing (Corcoran, 2015). Here, we evaluate the predictive value for psychosis onset, specifically of speed of face processing in CHR youths. METHODS: In a cohort of 49 CHR patients (of whom 7 later transitioned to psychosis), and 31 healthy controls, we examined reaction times for face processing using the UPenn battery, including the Emotion Recognition (ER-40; Kohler 2005), Emotion Discrimination (EMODIFF), Emotional Acuity (PEAT), Facial Identification, as well as motor praxis. RESULTS: CHR converters had significantly slower reaction time for face emotion recognition (FER) (p=.008), but not discrimination, acuity or facial identification. They also had slower motor praxis and greater baseline prodromal symptom severity (p

Background Early auditory processing (EAP) has increasingly become a focus of efforts to identify biomarkers of treatment response in schizophrenia. EAP deficits lead to poor functional outcome via impaired cognition, and treatments that target EAP may drive downstream cognitive improvements. Assessment of baseline need provides an opportunity for cognitive remediation (CR) programs that give EAP training to personalize treatment and optimize its impact. This initial efficacy study examined the differential benefit of EAP training for those with and without baseline EAP deficits as defined by performance on the Tone Matching Test. Methods 103 outpatient adults diagnosed with schizophrenia or schizoaffective disorder were classified as having intact (48.5%) or impaired (51.5%) EAP and randomized to a CR program with restorative exercise plans that either included EAP training (N = 49) or did not (N = 54). Cognitive and functional outcomes were measured post-treatment and 3 months later. Results Only in EAP impaired participants was there a significant benefit from EAP training on verbal learning. Treatment condition did not significantly impact global cognitive or functional outcomes for either EAP group. Cognitive gains partially mediated the relationship between gains in EAP and functional capacity. Conclusion These findings support the importance of addressing basic auditory deficits when attempting to remediate higher order auditory impairments such as verbal learning. In addition, they highlight the need for routine assessment of EAP in cognitive remediation participants, as well as the need for more effective programs to reverse these impairments.

Background Language offers a privileged view into the mind; it is the basis by which we infer others’ thoughts. Subtle language disturbance is evident in schizophrenia prior to psychosis onset, including decreases in coherence and complexity, as measured using clinical ratings in familial and clinical high-risk (CHR) cohorts. Bearden et al previously used manual linguistic analysis of baseline speech transcripts in CHR to show that illogical and referential thinking, and poverty of content, predict later psychosis onset. Then, Bedi et al used automated natural language processing (NLP) of CHR transcripts to show that decreased semantic coherence and reduction in syntactic complexity predicted psychosis onset. To determine validity and reproducibility, we have applied automated NLP methods, with machine learning, to Bearden’s original CHR transcripts to identify a language profile predictive of psychosis. Methods Participants in the Bearden UCLA cohort include 59 CHR, of whom 19 developed psychosis (CHR+) within 2 years, whereas 40 did not (CHR-), as well as 16 recent-onset psychosis and 21 healthy individuals, similar in demographics; speech was elicited using Caplan’s “Story Game. Participants in the Bedi NYC cohort include 34 CHR (29 CHR+), with speech elicited using open-ended interview. Speech was audiotaped, transcribed, de-identified and then subjected to latent semantic analysis to determine coherence and part-of-speech tagging to characterize syntactic structure and complexity. A machine-learning speech classifier of psychosis onset was derived from the UCLA CHR cohort, and then applied both to the NYC CHR cohort and to the UCLA psychosis/control comparison, with convex hull (three-dimension depiction of model) and receiver operating characteristics analyses. Correlational analyses with demographics, symptoms and manual linguistic features were also done. Results A four-factor model language classifier derived from the UCLA CHR cohort that comprised three semantic coherence variables and one syntax (usage of possessive pronouns) predicted psychosis t with accuracy of 83% (intra-protocol) for UCLA CHR, 79% (cross-protocol) for NYC CHR, and 72% for discriminating psychosis from normal speech (UCLA psychosis/control). Convex hulls were defined as the smallest space containing all datapoints within a set for CHR- or healthy controls: these convex hulls showed substantial overlap, with CHR+ and psychosis speech datapoints largely outside these convex hulls. Coherence was associated with age, but speech variables did not vary by gender, race, or socioeconomic status in this study. While automated text features were unrelated to prodromal symptom severity, they were highly correlated with manual text features (r = 0.7, p < .000001). Discussion In this small preliminary study, we identified and cross-validated a robust language classifier of psychosis risk that comprised measures of semantic coherence (flow of meaning in language) and syntactic usage (usage of possessive pronouns). This classifier had utility in discriminating speech in individuals with recent-onset psychosis from the norm. It demonstrated concurrent validity in that it was highly correlated with manual linguistic features previously identified by Bearden et al, important as automated methods are fast and inexpensive. Automated language features were unrelated to sex, ethnicity or social class in these small samples, and semantic coherence increased with age, consistent with prior studies of normal language development. Of interest, overlapping convex hulls could be defined for groups of individuals without psychosis (UCLA CHR-, NYC CHR- and UCLA healthy), suggesting a constrained hull of normal language in respect to syntax and semantics, from which pre-psychosis and psychosis speech deviates. The RDoC linguistic corpus-based variables of semantic coherence and syntactic structure hold promise as biomarkers of psychosis risk and expression, with initial validation and reproducibility. Next steps in biomarker development include larger multisite studies with standardization of protocols for speech elicitation, test-retest, and attention to traction/feasibility, acceptability, cost, and utility. Mechanistic studies can also yield neural and physiological correlates of abnormal semantic coherence and syntax.

Impairment in social cognition, including emotion recognition, has been extensively studied in both Autism Spectrum Disorders (ASD) and Schizophrenia (SZ). However, the relative patterns of deficit between disorders have been studied to a lesser degree. Here, we applied a social cognition battery incorporating both auditory (AER) and visual (VER) emotion recognition measures to a group of 19 high-functioning individuals with ASD relative to 92 individuals with SZ, and 73 healthy control adult participants. We examined group differences and correlates of basic auditory processing and processing speed. Individuals with SZ were impaired in both AER and VER while ASD individuals were impaired in VER only. In contrast to SZ participants, those with ASD showed intact basic auditory function. Our finding of a dissociation between AER and VER deficits in ASD relative to Sz support modality-specific theories of emotion recognition dysfunction. Future studies should focus on visual system-specific contributions to social cognitive impairment in ASD.

Deficits in auditory emotion recognition (AER) are a core feature of schizophrenia and a key component of social cognitive impairment. AER deficits are tied behaviorally to impaired ability to interpret tonal (“prosodic”) features of speech that normally convey emotion, such as modulations in base pitch (F0M) and pitch variability (F0SD). These modulations can be recreated using synthetic frequency modulated (FM) tones that mimic the prosodic contours of specific emotional stimuli. The present study investigates neural mechanisms underlying impaired AER using a combined event-related potential/resting-state functional connectivity (rsfMRI) approach in 84 schizophrenia/schizoaffective disorder patients and 66 healthy comparison subjects. Mismatch negativity (MMN) to FM tones was assessed in 43 patients/36 controls. rsfMRI between auditory cortex and medial temporal (insula) regions was assessed in 55 patients/51 controls. The relationship between AER, MMN to FM tones, and rsfMRI was assessed in the subset who performed all assessments (14 patients, 21 controls). As predicted, patients showed robust reductions in MMN across FM stimulus type (p= 0.005), particularly to modulations in F0M, along with impairments in AER and FM tone discrimination. MMN source analysis indicated dipoles in both auditory cortex and anterior insula, whereas rsfMRI analyses showed reduced auditory-insula connectivity. MMN to FM tones and functional connectivity together accounted for ∼50% of the variance in AER performance across individuals. These findings demonstrate that impaired preattentive processing of tonal information and reduced auditory-insula connectivity are critical determinants of social cognitive dysfunction in schizophrenia, and thus represent key targets for future research and clinical intervention.SIGNIFICANCE STATEMENTSchizophrenia patients show deficits in the ability to infer emotion based upon tone of voice [auditory emotion recognition (AER)] that drive impairments in social cognition and global functional outcome. This study evaluated neural substrates of impaired AER in schizophrenia using a combined event-related potential/resting-state fMRI approach. Patients showed impaired mismatch negativity response to emotionally relevant frequency modulated tones along with impaired functional connectivity between auditory and medial temporal (anterior insula) cortex. These deficits contributed in parallel to impaired AER and accounted for ∼50% of variance in AER performance. Overall, these findings demonstrate the importance of both auditory-level dysfunction and impaired auditory/insula connectivity in the pathophysiology of social cognitive dysfunction in schizophrenia.

Paying attention to visual stimuli is typically accompanied by event-related desynchronizations (ERD) of ongoing alpha (7-14 Hz) activity in visual cortex. The present study used time-frequency based analyses to investigate the role of impaired alpha ERD in visual processing deficits in schizophrenia (Sz). Subjects viewed sinusoidal gratings of high (HSF) and low (LSF) spatial frequency designed to test functioning of the parvo- versus magnocellular pathways, respectively. Patients with Sz and healthy controls paid attention selectively to either the LSF or HSF gratings which were presented in random order. Event-related brain potentials (ERPs) were recorded to all stimuli. As in our previous study, it was found that Sz patients were selectively impaired at detecting LSF target stimuli and that ERP amplitudes to LSF stimuli were diminished, both for the early sensory-evoked components and for the attend minus unattend difference component (the Selection Negativity), which is generally regarded as a specific index of feature-selective attention. In the time-frequency domain, the differential ERP deficits to LSF stimuli were echoed in a virtually absent theta-band phase locked response to both unattended and attended LSF stimuli (along with relatively intact theta-band activity for HSF stimuli). In contrast to the theta-band evoked responses which were tightly stimulus locked, stimulus-induced desynchronizations of ongoing alpha activity were not tightly stimulus locked and were apparent only in induced power analyses. Sz patients were significantly impaired in the attention-related modulation of ongoing alpha activity for both HSF and LSF stimuli. These deficits correlated with patients’ behavioral deficits in visual information processing as well as with visually based neurocognitive deficits. These findings suggest an additional, pathway-independent, mechanism by which deficits in early visual processing contribute to overall cognitive impairment in Sz.

Multisensory interactions are observed in species from single-cell organisms to humans. Important early work was primarily carried out in the cat superior colliculus and a set of critical parameters for their occurrence were defined. Primary among these were temporal synchrony and spatial alignment of bisensory inputs. Here, we assessed whether spatial alignment was also a critical parameter for the temporally earliest multisensory interactions that are observed in lower-level sensory cortices of the human. While multisensory interactions in humans have been shown behaviorally for spatially disparate stimuli (e.g. the ventriloquist effect), it is not clear if such effects are due to early sensory level integration or later perceptual level processing. In the present study, we used psychophysical and electrophysiological indices to show that auditory-somatosensory interactions in humans occur via the same early sensory mechanism both when stimuli are in and out of spatial register. Subjects more rapidly detected multisensory than unisensory events. At just 50 ms post-stimulus, neural responses to the multisensory 'whole' were greater than the summed responses from the constituent unisensory 'parts'. For all spatial configurations, this effect followed from a modulation of the strength of brain responses, rather than the activation of regions specifically responsive to multisensory pairs. Using the local auto-regressive average source estimation, we localized the initial auditory-somatosensory interactions to auditory association areas contralateral to the side of somatosensory stimulation. Thus, multisensory interactions can occur across wide peripersonal spatial separations remarkably early in sensory processing and in cortical regions traditionally considered unisensory.

The brain’s fascinating ability to adapt its internal neural dynamics to the temporal structure of the sensory environment is becoming increasingly clear. It is thought to be metabolically beneficial to align ongoing oscillatory activity to the relevant inputs in a predictable stream, so that they will enter at optimal processing phases of the spontaneously occurring rhythmic excitability fluctuations. However, some contexts have a more predictable temporal structure than others. Here, we tested the hypothesis that the processing of rhythmic sounds is more efficient than the processing of irregularly timed sounds. To do this, we simultaneously measured functional magnetic resonance imaging (fMRI) and electro-encephalograms (EEG) while participants detected oddball target sounds in alternating blocks of rhythmic (e.g., with equal inter-stimulus intervals) or random (e.g., with randomly varied inter-stimulus intervals) tone sequences. Behaviorally, participants detected target sounds faster and more accurately when embedded in rhythmic streams. The fMRI response in the auditory cortex was stronger during random compared to random tone sequence processing. Simultaneously recorded N1 responses showed larger peak amplitudes and longer latencies for tones in the random (vs. the rhythmic) streams. These results reveal complementary evidence for more efficient neural and perceptual processing during temporally predictable sensory contexts.

BackgroundBoth language and music are thought to have evolved from a musical protolanguage that communicated social information, including emotion. Individuals with perceptual music disorders (amusia) show deficits in auditory emotion recognition (AER). Although auditory perceptual deficits have been studied in schizophrenia, their relationship with musical/protolinguistic competence has not previously been assessed.MethodMusical ability was assessed in 31 schizophrenia/schizo-affective patients and 44 healthy controls using the Montreal Battery for Evaluation of Amusia (MBEA). AER was assessed using a novel battery in which actors provided portrayals of five separate emotions. The Disorganization factor of the Positive and Negative Syndrome Scale (PANSS) was used as a proxy for language/thought disorder and the MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognition.ResultsHighly significant deficits were seen between patients and controls across auditory tasks (p DiscussionThis is the first study to document a specific relationship between amusia, AER and thought disorder, suggesting a shared linguistic/protolinguistic impairment. Once amusia was considered, other cognitive factors were no longer significant predictors of AER, suggesting that musical ability in general and melodic discrimination ability in particular may be crucial targets for treatment development and cognitive remediation in schizophrenia.

Current treatments for schizophrenia function by blocking neurotransmission at dopamine D2 receptors. These compounds have proven highly effective for treatment of schizophrenia and especially for management of positive symptoms. A range of compounds and formulations are presently available, which permits tailoring of side effects to optimize treatment for individual subjects. Nevertheless, many patients suffer from persistent negative symptoms and neurocognitive deficits that contribute to persistent psychosocial impairments and long-term disability. At present, there are no approved pharmacological treatments for either negative symptoms or neurocognitive dysfunction. Instead, various behavioral approaches such as diet, exercise and cognitive remediation may be needed to help optimize cognitive function and mitigate symptoms. Furthermore, neuromodulation approaches, such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) are beginning to be employed both to minimize symptoms and to augment cognitive retraining approaches. At present, encouraging effects of tDCS on persistent auditory hallucinations have been reported, and if confirmed, may open the way for more widespread use of non-pharmacological treatments. At present, phase III studies remain ongoing for α7 nicotinic agonists in treatment of cognitive impairments and glycine reuptake inhibitors for suboptimal treatment response. Furthermore, preclinical studies suggest that glutamate-based treatment approaches may be effective if applied early in the illness. Future studies are needed to determine whether this will lead to effective approaches to halt illness progression for individuals at high clinical risk for schizophrenia.

Schizophrenia patients have deficits in cognitive function that are a core feature of the disorder. AX-CPT is commonly used to study cognition in schizophrenia, and patients have characteristic pattern of behavioral and ERP response. In AX-CPT subjects respond when a flashed cue “A” is followed by a target “X,” ignoring other letter combinations. Patients show reduced hit rate to “go” trials, and increased false alarms to sequences that require inhibition of a prepotent response. EEG recordings show reduced sensory (P1/N1), as well as later cognitive components (N2, P3, CNV). Behavioral deficits correlate most strongly with sensory dysfunction. Oscillatory analyses provide critical information regarding sensory/cognitive processing over and above standard ERP analyses. Recent analyses of induced oscillatory activity in single trials during AX-CPT in healthy volunteers showed characteristic response patterns in theta, alpha, and beta frequencies tied to specific sensory and cognitive processes. Alpha and beta modulated during the trials and beta modulation over the frontal cortex correlated with reaction time. In this study, EEG data was obtained from 18 schizophrenia patients and 13 controls during AX-CPT performance, and single trial decomposition of the signal yielded power in the target wavelengths. Significant task-related event-related desynchronization (ERD) was observed in both alpha and beta frequency bands over parieto-occipital cortex related to sensory encoding of the cue. This modulation was reduced in patients for beta, but not for alpha. In addition, significant beta ERD was observed over motor cortex, related to motor preparation for the response, and was also reduced in patients. These findings demonstrate impaired dynamic modulation of beta frequency rhythms in schizophrenia, and suggest that failures of oscillatory activity may underlie impaired sensory information processing in schizophrenia that in turn contributes to cognitive deficits.

Recent neuroscience advances suggest that when interacting with our environment, along with previous experience, we use contextual cues and regularities to form predictions that guide our perceptions and actions. The goal of such active “predictive sensing” is to selectively enhance the processing and representation of behaviorally relevant information in an efficient manner. Since a hallmark of schizophrenia is impaired information selection, we tested whether this deficiency stems from dysfunctional predictive sensing by measuring the degree to which neuronal activity predicts relevant events. In healthy subjects, we established that these mechanisms are engaged in an effort-dependent manner and that, based on a correspondence between human scalp and intracranial nonhuman primate recordings, their main role is a predictive suppression of excitability in task-irrelevant regions. In contrast, schizophrenia patients displayed a reduced alignment of neuronal activity to attended stimuli, which correlated with their behavioral performance deficits and clinical symptoms. These results support the relevance of predictive sensing for normal and aberrant brain function, and highlight the importance of neuronal mechanisms that mold internal ongoing neuronal activity to model key features of the external environment.

SummaryAlthough we have convincing evidence that attention to auditory stimuli modulates neuronal responses at or before the level of primary auditory cortex (A1), the underlying physiological mechanisms are unknown. We found that attending to rhythmic auditory streams resulted in the entrainment of ongoing oscillatory activity reflecting rhythmic excitability fluctuations in A1. Strikingly, although the rhythm of the entrained oscillations in A1 neuronal ensembles reflected the temporal structure of the attended stream, the phase depended on the attended frequency content. Counter-phase entrainment across differently tuned A1 regions resulted in both the amplification and sharpening of responses at attended time points, in essence acting as a spectrotemporal filter mechanism. Our data suggest that selective attention generates a dynamically evolving model of attended auditory stimulus streams in the form of modulatory subthreshold oscillations across tonotopically organized neuronal ensembles in A1 that enhances the representation of attended stimuli.

Perception has been identified by the NIMH-sponsored Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) group as a useful domain for assessing cognitive deficits in patients with schizophrenia. Specific measures of contrast gain derived from recordings of steady-state visual evoked potentials (ssVEP) have demonstrated neural deficits within the visual pathways of patients with schizophrenia. Psychophysical measures of contrast sensitivity have also shown functional loss in these patients. In the current study, functional magnetic resonance imaging (fMRI) was used in conjunction with ssVEP and contrast sensitivity testing to elucidate the neural underpinnings of these deficits. During fMRI scanning, participants viewed 1) the same low and higher spatial frequency stimuli used in the psychophysical contrast sensitivity task, at both individual detection threshold contrast and at a high contrast; and 2) the same stimuli used in the ssVEP paradigm, which were designed to be biased toward either the magnocellular or parvocellular visual pathway. Patients showed significant impairment in contrast sensitivity at both spatial frequencies in the psychophysical task, but showed reduced occipital activation volume for low, but not higher, spatial frequency at the low and high contrasts tested in the magnet. As expected, patients exhibited selective deficits under the magnocellular-biased ssVEP condition. However, occipital lobe fMRI responses demonstrated the same general pattern for magnocellular- and parvocellular-biased stimuli across groups. These results indicate dissociation between the fMRI measures and the psychophysical/ssVEP measures. These latter measures appear to have greater value for the functional assessment of the contrast deficits explored here.

The National Institute of Mental Health strategic plan for advancing psychiatric neuroscience calls for an acceleration of discovery and the delineation of developmental trajectories for risk and resilience across the lifespan. To attain these objectives, sufficiently powered datasets with broad and deep phenotypic characterization, state-of-the-art neuroimaging, and genetic samples must be generated and made openly available to the scientific community. The enhanced Nathan Kline Institute-Rockland Sample (NKI-RS) is a response to this need. NKI-RS is an ongoing, institutionally centered endeavor aimed at creating a large-scale (N > 1000), deeply phenotyped, community-ascertained, lifespan sample (ages 6–85 years old) with advanced neuroimaging and genetics. These data will be publically shared, openly, and prospectively (i.e., on a weekly basis). Herein, we describe the conceptual basis of the NKI-RS, including study design, sampling considerations, and steps to synchronize phenotypic and neuroimaging assessment. Additionally, we describe our process for sharing the data with the scientific community while protecting participant confidentiality, maintaining an adequate database, and certifying data integrity. The pilot phase of the NKI-RS, including challenges in recruiting, characterizing, imaging, and sharing data, is discussed while also explaining how this experience informed the final design of the enhanced NKI-RS. It is our hope that familiarity with the conceptual underpinnings of the enhanced NKI-RS will facilitate harmonization with future data collection efforts aimed at advancing psychiatric neuroscience and nosology.

Over the last 20 years, glutamatergic models of schizophrenia have become increasingly accepted as etiopathological models of schizophrenia, based on the observation that phencyclidine (PCP) induces a schizophrenia-like psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews developments in two key predictions of the model: first, that neurocognitive deficits in schizophrenia should follow the pattern of deficit predicted based on underlying NMDAR dysfunction and, second, that agents that stimulate NMDAR function should be therapeutically beneficial. As opposed to dopamine receptors, NMDAR are widely distributed throughout the brain, including subcortical as well as cortical brain regions, and sensory as well as association cortex. Studies over the past 20 years have documented severe sensory dysfunction in schizophrenia using behavioral, neurophysiological, and functional brain imaging approaches, including impaired generation of key sensory-related potentials such as mismatch negativity and visual P1 potentials. Similar deficits are observed in humans following administration of NMDAR antagonists such as ketamine in either humans or animal models. Sensory dysfunction, in turn, predicts impairments in higher order cognitive functions such as auditory or visual emotion recognition. Treatment studies have been performed with compounds acting directly at the NMDAR glycine site, such as glycine, D-serine, or D-cycloserine, and, more recently, with high-affinity glycine transport inhibitors such as RG1678 (Roche). More limited studies have been performed with compounds targeting the redox site. Overall, these compounds have been found to induce significant beneficial effects on persistent symptoms, suggesting novel approaches for treatment and prevention of schizophrenia.

Schizophrenia is associated with perceptual and cognitive dysfunction including impairments in visual attention. These impairments may be related to deficits in early stages of sensory/perceptual processing, particularly within the magnocellular/dorsal visual pathway. In the present study, subjects viewed high and low spatial frequency (SF) gratings designed to test functioning of the parvocellular/magnocellular pathways, respectively. Schizophrenia patients and healthy controls attended to either the low SF (magnocellularly biased) or high SF (parvocellularly biased) gratings. Functional magnetic resonance imaging (fMRI) and recordings of event-related potentials (ERPs) were carried out during task performance. Patients were impaired at detecting low-frequency targets. ERP amplitudes to low-frequency gratings were diminished, both for the early sensory-evoked components and for the attend minus unattend difference component (the selection negativity), which is regarded as a neural index of feature-selective attention. Similarly, fMRI revealed that activity in extrastriate visual cortex was reduced in patients during attention to low, but not high, SF. In contrast, activity in frontal and parietal areas, previously implicated in the control of attention, did not differ between patients and controls. These findings suggest that impaired sensory processing of magnocellularly biased stimuli lead to impairments in the effective processing of attended stimuli, even when the attention control systems themselves are intact.

Purpose of review The past 20 years have seen the glutamatergic hypothesis go from theory to phase III trials of novel mechanism antipsychotics. Recent findings We review the recent literature on glutamatergic theory, covering assessment and genetic studies, as well as drug development in animals and humans. Summary Although evidence continues to accumulate in support of glutamate hypotheses, further research continues to be required and interactions with other key systems need to be explored.

Current research has shown that the magnocellular system may play a crucial role in reading deficits related to dyslexia. The current study explored the relationship between magnocellular activity and reading abilities; we examined the hypothesis that a repeated usage of the magnocellular stream may improve reading by strengthening crucial neural pathways. Visual training was conducted for five consecutive days using a motion detection task (magnocellular training) and a control task of pattern detection (parvocellular training). Reading abilities of skilled readers were measured before and after the training using a lexical decision task. It was found that low grade visual training overall can improve speed of lexical decision, but only magnocellular training selectively improved accuracy. Improvement in the magnocellular training task predicted performance on adjacent anagram and word recognition after training. In contrast, in the control group (parvocellular training) degree of improvement in training did not predict lexical decision performance after training. This result lends support to the role of the magnocellular system in reading, and has potential implications for neuro-rehabilitation of reading related deficits.